Bradykinin is an endogenous nonapeptide which is thought to play an important role in a variety of inflammatory diseases and pain. Bradykinin (BK) and the decapeptide kallidin are released from plasma and tissue protein kininogens by the proteolytic action of kallikreins. Kinins are also produced during acute inflammation following the release of cellular proteases from immune cells. Rapid degradation of bradykinin and kallidin occurs through kininase activity to yield several active and inactive metabolites such as des-Arg9-bradykinin and des-Arg10-kallidin (Bhoola K et al. Pharmacology Reviews 1992, 44, 1-80).
Bradykinin itself has been shown to induce pain by direct stimulation of nociceptors (C and Aδ fibers) which innervate most tissues such as skin, joint and muscle. These sensory fibers then become sensitized to various physical and chemical stimuli. Bradykinin may sensitize fibers by synergistic interactions with other inflammatory agents such as prostaglandins or by the release of histamine from mast cells (Nicol G and Cui M J. Physiol. 1994, 480, 485-92). 
In mammals, the biological effects of kinins are mediated through two distinct bradykinin receptor subtypes, B1 and B2. Both B1 and B2 receptors are members of the superfamily of G-protein coupled receptors (Dray A. and Perkins M. Trends in Neurosciences 1993, 16, 99-104). Bradykinin B2 receptors have high affinity for bradykinin and kallidin and are constitutively expressed in contrast to bradykinin B1 receptors which are inducible. B2 receptors are largely distributed in peripheral and central tissues and are present in neurons, endothelial cells, epithelial cells and fibroblasts. Both B1 and B2 receptors have been cloned in many animal species as well as human.
Many of the physiological actions of kinins seem to be mediated by stimulation of the constitutive BK B2 receptor. Because of the important role that kinins are believed to play in a variety of inflammatory diseases and pain, researchers have pursued antagonists for the kinin receptors for years. Potent and selective peptide antagonists, specific for the B2 receptor, were discovered and evaluated in the clinic (Hock et al, British Journal of Pharmacology 1991, 102, 769; Cheronis et al, Journal of Medicinal Chemistry 1992, 35, 1563). Data collected with these antagonists supported the idea that an increase in endogenous kinins may be involved in inflammation, pain and tissue injury, These non-peptide BK2 antagonists also allowed researchers to further investigate the role that kinins play in vascular disease states such as arteriosclerosis (Hoechst AG, EP-007977997 (1997)).
In 1993, Sterling-Winthrop published their findings on a non-peptide bradykinin B2 receptor antagonist, WIN 64338 (Salvino J, Seoane P. and Douty B. Journal of Medicinal Chemistry 1993, 36, 2583). There were a number of drawbacks to this series of compounds including low specificity and a species-dependent variable affinity for kinin receptors.
Recently several novel classes of non-peptide bradykinin B2 receptor antagonists were disclosed by Fujisawa (Oku T, Kayakiri H, Satoh S, Abe Y and Tanaka H EP 596406 (1994); Oku T, Kayakiri H, Satoh S, Abe Y and Tanaka H EP 622361 (1994); Inamura N, Asano M and Hatori C et al. European Journal of Pharmacology 1997, 333, 79; Asano M, Inamura N And Hatori C et al. British Journal of Pharmacology 1997, 120, 617.) These compounds possess high affinity and specificity for the bradykinin B2 receptor. They were also shown to exhibit in vivo functional antagonist activity. (Abe Y, Kayakiri H and Satoh S et al Journal of Medicinal Chemistry 1998, 41, 564; Abe Y, Kayakiri H and Satoh S et al Journal of Medicinal Chemistry 1998, 41, 4053; Abe Y, Kayakiri H and Satoh S et al Journal of Medicinal Chemistry 1998, 41, 4062: Abe Y, Kayakiri H and Satoh S et al Journal of Medicinal Chemistry 1998, 41, 4587).
In PCT publication WO 97/41104 and U.S. Pat. No. 6,083,959, Oku, T. et al disclosed bradykinin modulating compounds of the formula:                 wherein:                    R1 is lower alkyl,            R2 is hydrogen, lower alkyl or a heterocyclic group,            R3 is hydrogen, lower alkyl or halogen,            R4 is lower alkyl or halogen,            R5 is nitro or amino substituted with substituent(s) selected from the group consisting of lower alkyl and acyl, and            A is lower alkylene, provided that R3 and R4 are each lower alkyl when R2 is hydrogen or lower alkyl.The acyl group of R5 is further defined as including optionally substituted heterocyclic(lower)alkanoyl moieties, in which the term heterocyclic includes unsaturated 3- to 8-membered, preferably 5- or 6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms or a sulfur atom.                        
Oku T, Kayakiri H, Abe Y, Sawada Y and Mizutani T, in PCT publication WO 97/11069 disclosed bradykinin modulating compounds of formula:                 wherein:                    A1 is lower alkylene,            R1 is substituted quinolyl, etc.,            R2 is hydrogen, halogen or lower alkyl, and            R4 is a group of the formula —Q—A2—R5, etc. in which                            R5 is amino, acylamino, etc.,                A2 is lower alkylene or a single bond, and                Q is a group of formula (a), etc.                                                
In U.S. Pat. No. 5,574,042, Oku, T et al disclosed imidazo[1,2-a]pyridines having the formula:                 wherein:                    R1 is halogen,            R2 and R3 are each hydrogen, lower alkyl, halo(lower)alkyl or acyl,            R4 is aryl having suitable substituent(s), or a heterocyclic group optionally having suitable substituent(s),            Q is O or N—R11, in which R11 is hydrogen or acyl, and            A is lower alkylene.The suitable substituents on the aryl group of R4 are further defined as including acyl groups, which is further defined to include optionally substituted heterocyclic(lower)alkanoyl moieties, in which the term heterocyclic includes unsaturated 3- to 8-membered, preferably 5- or 6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms or a sulfur atom.                        
In PCT publication WO 96/13485, Oku, T. et al disclose pyridopyrimidones, quinolines and fused N-heterocyclic compounds as bradykinin modulators.
A number of derivatives that are structurally related to the Fujisawa compounds have been disclosed by Fournier (Dodey P, Bondoux M, Pruneau D et al. WO 96 40639 (1996); Dodey P, Bondoux M et al. WO 97 07115 (1997); WO 97 24349 (1997); WO 98 03503 (1998) and also by Hoechst (Heitsch H, Wagner A, Wirth K et al. EP 795547 (1997); EP 796848, EP 835659 (1998).
Compounds of the present invention have not been previously disclosed or enabled.
It is expected that bradykinin receptor antagonists may be useful in the treatment and prevention of various mammalian disease states, for example pain, inflammatory joint disease, inflammatory bowel disease, allergy, asthma, rhinitis, brain edema and trauma, tissue injury, septic shock, acute pancreatitis, post-operative pain and migraine. It is also expected that bradykinin receptor agonists may be useful in the treatment and prevention of other disease states such as hypertension and the like.
It is an object of the present invention to provide bradykinin (B2) receptor modulators. It is a further object of the invention to provide bradykinin antagonists and bradykinin agonists. It is an object of the present invention to provide a method of treating or ameliorating a condition mediated by the bradykinin receptor. It is an object of the invention to provide a useful pharmaceutical composition comprising a compound of the present invention useful as bradykinin modulators